Virus infections are on the rise. Although the first description of CYP expression during virus infection was recorded 50 years ago, mechanistic studies of this phenomenon only began to appear in the last decade due to breakthroughs in molecular biology, genomic and transgenic technology. This review describes the relationship(s) among CYP-mediated drug metabolism, virus infection and the immune response and evaluates in vitro and in vivo models for mechanistic studies. The first studies that assessed CYP expression during infection focused on inflammatory mediators and the innate immune response at early time points. Recent studies assessing virus infection and its effect on hepatic CYP expression noted more long-term effects. An obvious approach toward understanding how viruses affect hepatic CYP3A expression and function would be to assess key regulators of CYP during infection. Improvements in techniques to identify post-translational modifications of CYP and systems that focus on virus-receptor interactions which allow subtraction and addition of immunological and regulatory elements that drive CYP will demonstrate that long-term changes in drug metabolism start from the time the virus enters the circulation, are reinforced by virus binding to cellular targets and further solidified by changes in cellular processes long after the virus is cleared.